Download MendeleyThe Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to beta-Lactams.
Stubbs, K.A., Bacik, J.P., Perley-Robertson, G.E., Whitworth, G.E., Gloster, T.M., Vocadlo, D.J., Mark, B.L.(2013) Chembiochem 14: 1973-1981
- PubMed: 24009110
- DOI: https://doi.org/10.1002/cbic.201300395
- Primary Citation of Related Structures:
4HZM - PubMed Abstract:
The increasing incidence of inducible chromosomal AmpC β-lactamases within the clinic is a growing concern because these enzymes deactivate a broad range of even the most recently developed β-lactam antibiotics. As a result, new strategies are needed to block the action of this antibiotic resistance enzyme. Presented here is a strategy to combat the action of inducible AmpC by inhibiting the β-glucosaminidase NagZ, which is an enzyme involved in regulating the induction of AmpC expression. A divergent route facilitating the rapid synthesis of a series of N-acyl analogues of 2-acetamido-2-deoxynojirimycin is reported here. Among these compounds are potent NagZ inhibitors that are selective against functionally related human enzymes. These compounds reduce minimum inhibitory concentration values for β-lactams against a clinically relevant Gram-negative bacterium bearing inducible chromosomal AmpC β-lactamase, Pseudomonas aeruginosa. The structure of a NagZ-inhibitor complex provides insight into the molecular basis for inhibition by these compounds.
Organizational Affiliation:
School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009 (Australia). [email protected].
